CA1237539A

CA1237539A - Dosimetry system for strontium-rubidium infusion pump

Info

Publication number: CA1237539A
Application number: CA000447508A
Authority: CA
Inventors: Brian C. Bergner; Samuel L. Barker; Michael D. Loberg
Original assignee: ER Squibb and Sons LLC
Current assignee: Bracco International BV
Priority date: 1983-02-28
Filing date: 1984-02-15
Publication date: 1988-05-31
Also published as: DE3482410D1; EP0117752A2; AU570429B2; US4585941A; JPH05249245A; EP0310148A2; JPH0562314B2; EP0117752B1; JPS59163584A; US4585009A; ATE53305T1; AU2464684A; EP0310148A3; EP0117752A3

Abstract

ABSTRACT

A strontium-rubidium infusion system gen-erates Rubidium 82 in a solution and infuses this solution into a patient. The amount of solution in-fused is controlled in response to measurements of the radioactivity which has been infused.

Description

~ ;~3'753~3 The present invention relates to a stron-tium-rubidium infusion system. In particular, it provides a strontium-rubidium infusion system which has a means of generating Rubidium 82 in a solution which can be infused into a patient, and means for infusing the solution into the patient in a con-trolled manner.
Current statistics show that approximately one-third of all deaths in the United States are re-lated to coronary artery disease. See, for example,Pohost, G., McKusick, K., and Strauss, W., "Physio-logic Basis and Utility of Myocardial Perfusion Im-aging" Proceedings of the Second International Sympos-ium on Radiopharmaceuticals, Society of Nuclear Med-icine, New York 1979, pp. 465-473, and this fact has prompted extensive research to more efficiently diag-nose and manage this disease. Recent advances in radiopharmaceutical development and instrument design have established myocardial scintigraphy as an impor-tant new approach for evaluating coronary artery dis-ease and myocardial perfusion. See, for example, Pierson, R., Friedman, M., Tansley, W., Castellana, F., Enlander, D., and Huang, P., "Cardiovascular Nu-clear Medicine: An Overview", Sem. Nucl. Med., 9, 224-240 (1979)i Leppo, J., Scheuer, J., Pohost, G., Freeman, L., and Strauss, H., "The Evaluation of Ischemic Heart Disease Thallium-201 with Comments on Radionuclide Angiographylli Sem. Nucl. Med., 10, 115-126 (1980); Vogel, R., "Quantitative Aspects of Myo-cardial Perfusion Imaging", Sem. Nucl. Med., 10, 146-156 (1980); Chervu, R., "Radiopharmaceuticals in Car-diovascular Nuclear Medicine", Sem. Nucl. Med., 9, 241-256 (1979); and Pitt, B., and Strauss, H., "Car-diovascular Nuclear Medicine", Sem. Nucl. Med., 7, 3-6 (1977).

Myocardial scintigraphy studies have been performed with several isotopes of potassium, rubidium, 5 cesium, and thallium (Tl-201), although the usefulness of all of these nuclides ie limited by their non-optimal physical p~operties. In spite of its long half-life and low-gamma energy, T1-201 i5 currentlv the most widelv used agent for myocardial imaging. See, for example, Poe, N., "Rationale and Radiopharmaceuticals for Myocardial Imaging", Sem. Nucl. Med., 7, 7-14 (1977);
Strauss, H. and Pitt, B., "Thallium-201 as a Myocardial Imaging Agent", Sem. Nucl. Med., 7, 49-58 (1977);
Botvinick, E., Dunn, R., Hattner, R., and Massie, B., "A
Consideration of Factors Affecting the Diagnostic Accuracy of Tl-201 Myocardial Perfusion Scinti~raphy in Detectiny Coronary Artery Disease", Sem. Nucl. Med., 10, 157-167 (1980~; and Wa~kers, F., "Thallium-201 Myocardial Scintigraphy in Acute Myocardial Infarction and Ischemial', Sem. Nucl. Med., 10, 127-145 (1980).
In diagno~tic procedures in which the heart is involved, it is desirable for a diagnostician to be able to view a patient's heart. Heretofore, va~ious radioactive materials have been used ~ogether with radiological procedures for viewing internal o~gans of patients. It has been difficult, however, to view a heart because the radioactive substances which could be used for viewing the heart have had a very long half-life. Thus, using them with patients involves an element of danger and also reduces the number of times that a patient could be infused within any given time period. It would therefo~e be desirable to have a diagnostic apparatus and procedure which could be used with relative safety for viewing the heart.
Rubidium-82 is a potassium analog. That means 7~3~

l ~ RB70 it acts similar to potassium when it is infused into a patient. ThUc it builds up at a very rapid rate, i.e., S within seconds, in the patient' 6 heart. Rubidium-82 also has the advantage of having a very short half-life, approximately 76 seconds. Therefore, it decays after a very short period of time following entry into the body, thereby allowing numerous procedures to be performed within a relatively short time period in a given patient. Rubidium-82 also has the advantage of being observable using a modified gamma camera such as a gamma camera of the type manufactured by Searle Radiographics, Inc., called the P~0 Gamma IV. A problem with usin-g lS Rubidium-82 in a patient involves keeping track of the amount of radiation infused into the patient. In view of the very short half-life of Rubidium-82, it is impractical to measure the radioactivity of a particular dose and to then infuse it into the patient using conventional means. An accurate method for measuring the amount of radiation being infused into the patient would be highly desirable for this particular application.
The availability of improved instrumentation has stimulated intersst in the use of the positron emitter, Rubidium-82, for myocardial imaging. See for example, Beller G., and Smith, T., "Radionuclide Techniques in the Assessment of Myocardial Ischemia and Infarction," Circulation, , 53 (3, Supp. l) 123-125 (1976); Budinger, T., Yano, Y., Derenzo, S., et al., "Myocardial Uptake of Rubidium-82 Using Positron Emission Tomography," J., Nucl. Med. 20, 603 (1979);
Budinger, T., Yano, Y., Derenzo, S., et al., "Infa~ction Sizing and Myocacdial Perfusion Measurements Using Rb-82 3s and Positron Emission Tomography," Amer. J. Cardiol..

~:3~539 45, 399 (1980). Rubidium-82. an analog of the alkali metal potassium, is rapidly cleared from the blood and concentrated by the myocardium. The short half-life of the Rubidium-52 (76 sec) offers the unique advantage of permitting repeat perfusion and blood flow studies in patients whose clinical status is rapidly changing.
Rubidium-82 is produced by the decay of its parent, strontium-~2. E. R. Squibb and Sons, Inc. has developed a Rubidium-82 generator and infusion system which yields an isotonic saline solution of Rubidium-82 at physiological p~ for rapid administration. In animal experiments, the safety and myocardial uptake of Rubidium-82 has been demonstrated. ~herefore this agent has been selected as a candidate for clinical trials.

In the Drawing:
FIG. 1 is an overall schematic diagram of the strontium-~ubidium infusion system used in conjunction with the present invention;
FIG. Z is a front view of the infusion pump control used with the strontium-rubidium infusion system;
FIG. 3 i6 a front view of the dosimetry control u~ed with the strontium-rubidium infusion system;
FIG. 4 is a graph of radioactivity measured (on the y-axis) by the dosimeter probe versus time ~on the x-axis);
FIG. 5 is a perspective view of the dosimetry probe;
FIG. 6 is a schematic diagram of the interface between the dosimetry probe of FIG. 4 and the dosimetry control circuitry:
FIG. 7 is a schematic diagram of the circuit for the Single Channel Analyzer used to convert and ~3~ 9 _5_ ~hape the raw pulse6 from the do6imetry probe of FIG. 4 PIG. 8 i6 a schematic diagram of the circuit S f or the Multiply-Divide circuit used to carry out -the formula which converts pul5es from the Single Channel Analyzer into radioactivity present in front of the dosimet~y probe:
FIG. 9 i6 a schematic diagram of one of the Display Controller circuit~ ufied to interface the switches and the displays to the other circuitry:
FIG. 10 i6 a 6chematic diagram of the Dose Rate circuit used to provide a display of the amount of radiation pre6ent in the eluate;
~IG. 11 is a schematic diagram of the Control Circuit which oversees the operation of the remainder of the ciLcuitry; and FIG. 12 i6 a schematic diagram of a valve driver circuit.
Referring now ~o FIG. 1, a saline bag 10 is connected, through a bullet nose fitting 12 and a piece of tubing 14, to a T-shaped two-way check valve 16 having three arms. ~ first arm 20 includes a one-way valve which permit6 saline to enter the check valve 16, but doe~ not allow it to éxit back into the tubing 14.
A second arm 22 includes a check valve which permits ~aline to exit from the check valve 16 into a filter 24 through a tube 26, but doe6 not allow it to re-enter the c~eck valve 16 from the tube 26. A syringe 18, connected to the check valve 16 fills from the saline bag 10 and pumps out through the tubing 26 into the filter ~4. Saline pumped through the filter 24 enters a ~trontium-rubidium generator 28 which is of the tyPe described more fully in C~dian Patent No, 1,171,354 1~3~7X~

dated July 24, 1984, entitled RB GENERATING METHOD AND
ELUENT.
Saline pumped through the strontium-rubidium generato~ 28 exits the generator 28 through tubing 30 containing Rubidium-82. The tubing 30 is connected to a diverter valve 32 having a fir~t ar~ 34 which leads through tubing 38, an antibacterial filter 40, and ultimately to waste 42. A second arm 35 of the diverter valve 32 is connected through tubing 44, an antibacterial filter 48, additional tubing 50, and into an infusion needle 52. The infusion needle 52 is typically inserted into the aIm 54 of a patient 56.
In the preferred embodiment of the invention, the check valve 16 is a dual back check valve of the type made by Beckton Dickenson Inc.. and the antibacterlal filters are of the type made by Schleicher ~ Schull a6 their type FP030/3.
ln the operation of the device, the amount of radioactivity in the saline eluted from the strontium-rubidium generator 28 ~ust be measured as it is introduced into the patient 56. Accordingly, a dosimetry pLobe 58 is placed adjacent to the tubing 30 where it measures the radioactivity of the rubidium-containing saline as it leaves the generator 28 and enters the diverter valve 32.
In order to use the infusion system, various procedures must be performed and controlled. In pa{ticular, the syringe 18 must be purged of air, and filled with saline, and the diverter valve 32 must be positioned. These operations ire contingent upon a number of factors including the total volume to be infused into the patient 56, the total dosage to be .~

1~37539 . --7--infu6ed into the patient s6, the minimum radioactivity which must ~e present in the tubing 30 before any eluate i~ infused into the patient 56, the total volume to be infused (Note: The total volume eluted may differ from the total volume infused into the patient 56 a~ some volume i8 likely to be diverted to waste.~
The foregoing parameters may be altered from the front panel of two different controllers shown in PIGS. 2 and 3~ These are the infusion pump controller 60 and the dosimetry controlle~ 62, repectively. The infusion pump cont~oller 60 controls the mechanical movement of the syringe's plunger 66 via a stepping motor 64 which is connacted to the plunger 66.
In the preferred embodiment of the invention.
the syringe 18 is a sterile, d~sposable plastic syringe of the type made by Sherwood Medical and designated as Part. No. 881-514031. The infusion pump controllec 60 limits the movement of the syringe plunger 66 based upon optical limit detectors 68, 70 which limit the fully displaced and ~ully extended positions of the plunger 66, respectively. The volume control function performed by the infusion pump controller 60 i8 accomplished by counting the number o~ pulses sent to the stepping motor 64.
With reference to PIG. 2, the front panel of the in~us~on pump cont~oller 60 is shown. The infusion pump controller 60 includes an on/off power switch 72 which is used to turn on the power to the unit.
A set of thumbwheel switches 74 is used to select the total volume ~ml) to be eluted. An LED
display 76 shows the total volume (ml) which has been eluted. A momentary contact push-button 6witch 78 is used to start and to stop the movement of the plunger 66 3~33 in the forward (inject) direction.
A set of push-button potentiometeLs comprise the Flow Rate Control 80 which is used to determine the volume per unit time which is infused. The Flow Rate Control 80 sets the pulse rate into the stepping motor 64. An LED 82 lights when the end of travel of the plunger 66, as indicated by the optical limit detectors 68, 70 is reached. A pair of momentary contact push-button switches 84, 86 are used to control the purge and refill functions, respectively, of the syringe 1~. Thus, if the purge control switch 84 is pushed, and held, the plunger 66 continues to move in the forward direction until it reaches the forward limit detector 68. Similarly, while the refill control switch 84 is pressed and held, the plunger 66 conCinues to move toward the rear limit detector 70. The speed of movement of the plunger 66 during purge and refill operations are control*ed by adjustable screw-type potentiometers 88, 90, respectively.
The infusion pump controller 60 i8 comprised of a Superio~ Electric Company STM103 Translator Module which is interfaced to provide signals representative of flow rate, volume eluted, and injection. It i6 also interfaced to be remotely controlled. A pulse called "INIT" indicates that the Translator Module has been powered. The "INIT" pulse is used to reset the displays on the dosimetry module. An "INJECT~' signal indicates that the pump is injecting. Output pulses, corresponding to .1 ml steps of the syringe 18, are provided. An ~'End of Elution" signal is used to ~emotely disable the infusion pump controller 60.
With reference now to FIG. 3, the dosimetry controller 62, is comprised of a number of LED displays 37~39 _9_ and thumbwheel switch sets. In addition, the dosimetIy controller 62 includes an on/off switch 92 for providing power to the unit.
The fir~t set of thumbwheel switches 94 is used to set the volume (ml) to be infused into the patient 56. The LED display 96, immediately above the thumbwheel switches 94, displays the volume of eluate which has been infused into the patient 56.
The thumbwheel switches 98 are used to set the total dose (mCi) which is to be infused into the patent 56 and the LED display 100 immediately above the total dose thùmbwheel switches 98 displays the total dose which has been infused into the patient 56. Similarly, the thumbwheel switches 102 are used to set the dose rate (mCi~sec.) which i8 to be used to dete~mine when to 6witch the diverter valve 32 from the waste position to the patient 56 position. The actual dose rate which is present in the eluate within the tube 30 in front of the dosimetry probe 58 i~ displayed on the LED display 104.
The description of the dose present in the eluate at any given time from the start of infusion will be provided hereafter, The dosimetry controller 62 further compriges a pair of LED's 106, 108 which indicate the position of the diverter valve 32. Only one of these two LED's 106, 108, should be on at any given time.
While the normal position of the diverter valve 32 is toward waste, except when eluate is being infused into a patient 56, provision must be made to clear the tubing 44. 50 of any air prior to infusing a patient 56. Accordingly, the dosimetry controller 62 includes a toggle switch 110 which is used to haLd wire the diverter valve 32 in the patient 56 position.
' The present preferred embodiment of the 7~3~

invention also includes a set of thumbwheel swit~hes 112 which are used to set the flow rate which will be used in internal calculations of dosimetry controller 62. It is presently anticipated by the inventor that a future version of the present invention will include automatic means for deter~ining the flow rate based upon the settings used in the infusion pump controller 60.
10Referring now to FIG. 4, a graph of the radioactive aosaqe present in the tubing 30 in front of the dosimetry probe 58, is shown. In the graph, the dosage is measured on the y-axis and time i~ measured on the x-axis. The time is referenced with zero being the time that the start/stop inject button 78 on the infusion controller 60 is pushed to commence infusion.
Por approximately 10 seconds there will be no radioactivity present in the eluate from the strontium-rubidium generator 28. Thereafter, the do~e rate rises at a rapid rate up to a maximum, after which the dose rate falls to a level value indicative of the steady state regeneration rate of the Sr-Rb generator 28, Thus, when the infusion starts, there is a delay initially as the dose rate build~ up, a reduction in dosage after the generator 28 is par~ially eluted, and the~ there is a dosage representative of the steady state regeneration rate of the generator 28.
The setting of the dose rate thumbwheel switches 102 tells the dosimetry controller 62 at what point along the upward slope of the dosage curve to switch the diverter valve 32 from the waste position to the patient 56 position whereby the eluate will be infused into the patient 56. At that point the dose indicated by the LED's 100 will start accumulating from zero, where it had been until that point. Similarly, ~237~i3~3 the patient 56 volume indicated by the LED' 6 96 will start to accu~ulate as of that time.
once eluate is infused into the patient 56, it continues to be infused until one of various stop indications occurs. In particular, when the total patient 56 dose, set by the thumbwheel switches 98, is reached, the diverter valve 32 i8 returned to the waste position, and the stepping motor 64 stops, thereby preventing further infusion. Similarly, the diverter valve 32 is switched, and the stepping motor 64 is stopped when the patient 56 volume, preset by the thumbwheel switches 94 reaches its preset value or after L5 the total volume to be eluted, set by the volume thumbwheel switches 74 reaches its.preset value; Qr when the purge limit optical stop 68 of the syringe 18 is reached: or if the start/stop inject button 78 is pushed. Any o~ the foregoing events causes the diverter valve 32 to switch to the was~e position, and causes the stepping motor 64 to 6top. Note, however, that the purge and refill switches 84, 86 are disabled as of the time that the start~stop inject button 78 is pushed to commence the infusion.
Ouantizinq Radioactivitv in a Liquid Stream In order to measure the radioactivity in the saline solution which passes through the line 30 in ront o the do6imetry p~obe 58, it i8 necessary to count the number of disintigrations which occur in front of the probe 58, while at the same time keeping t~ack o the 10w rate of the saline through the tube 30. Given that these guantities are known, it is possible to measure the total activity in milliCuries (mCi) in accordance with the following formula:
A (V)(E)(CM)(Y) Where, A = total activity (mCi):
C = net counts:
F , flow rate (ml/min):
V , volume in detector view (ml);
E = net efficiency (counts per minuteJdisintegration per minute): -C~ = disintegrations/minute to milliCurie conversion factor: and Y = net yield of photon.
15 In the case of the present invention, the above fo~mula can be simplified to:
A lCl(F) wnere, A _ total activity (in milliCuries);
C . net counts (from p~obe);
20 F 5 the flow rate; and K ~ the calibration factor.
As noted, the calibration factor, K, takes into account the volume in the detector's view, the net efficiency of the probe, the conversion factor in terms of disintigrations per minuta to milliCuries, and the net- yield of photons. These factors are substantially constant for any given probe and tubing combination for a ~easonable amount of time. Accordingly, p~ovision is made on the circuit board to adjust the calib~ation factor, K, when the instrument is serviced. However, the calib~ation factor~ K, is not user adjustable in the normal course of ope~ation.
Dosimetrv Pcobe Refe~ring now to FIG. 5, the dosimetry probe 58 is comprised of a photomultiplier tube 120, such as the 1~3753~ .

RCA C~3009E 14 mm diameter 10-stage photomultiplier tube manufactured by the ~lectro 0ptics Division of ~CA
Corporation ~n Lancaster, Pennsylvania. The photomultiplie~ tube 120 has a face 122 through which input signals in the form of light are received. On the face 122, a plastic scintillator 124, such as a Nuclear Enterpri6es Type 102A manufactured in Edinburgh, Scotland, i6 mounted. In the preferred embodiment o~
the invention, the plastic scintillator 124 is glued or bonded to the face 122 of the photomultiplier tube 120.
After the plastic scintillator 124 has been bonded to the face 122 of the photomultiplier tube 120, an aluminum foil covering (not shown) is placed over the face end of the photomultiplier tube 120, including the plastic scintillator 124. The purpose of the aluminum foil covering is to reflect back into the tube 120 any light which scintillates from the plastic scintillator 124 away from the tube 120. In addition, the aluminum ~oil covering prevents any stray light which might come into the area of the face 122 from getting into the tube 120. Following the application of the aluminum foil, a light tight material, such as black electrical tape is wrapped ove~ the aluminum foil covered tube 120 in order to further prevent any light from entering into the tube 120. The tape-wrapped tube 120 is then inserted into a mu metal shield 126 which is intended to prevent any electromagnetic radiation effects from affecting the output of the dosimetry probe 58. In the preferred e~bodiment of the invention, the dosimetry probe 58 is plugged into a standard photomultiplier tube socket base 128 containing a standard resistive biasing network.

1~37~3~3 Dosimetrv circuitrY
Referring now to FIG. 6, the photomultiplier S tube socket base 128 includes a resistive networlc containing biasing resistors for placing appropriate bias voltages on the ten dynodes in the photomultiplier tube 120. Accordingly, the high voltage connection to the photomultiplier tube base 128 is automatically 10 biased to provide appropriate operating voltages to the photomultiplier tube 120. The high voltage supply 130 used in the~ preferred embodiment of the invention is a 0-1000 volt, adjustable Bertan PMT-lOA-P power supply manufactured by Bertan Associates, Inc., Three Aecial 15 Way, Syosset, New York. In the present application, the high voltage supply 130 is adjusted to provide an output voltage of 950 volts. The photomultipler tube socket base 128 i8 an RCA photomultipler tube soclcet base, Part No. AJ2273.
An output siqnal goes from the dosimetry probe 58 on a line 132 to a coupling network comprising a pull up resistor 134, a coupling capacitor 136, and a output resistor 138. Accordingly, an AC signal having a peak to peak maximum of approximately 250 millivolts with 25 negative goina pulses, is provided on output line 140.
Sinqle Channel AnalYzer Referring now to FIG. 7, the schematic diagram for a Single Channel Analyzer circuit is shown. The Single Channel Analyzer is used, because the pulses on 30 output line 140 from the Dosimetry circuitry are very shacply defined pulses which may occur at very high frequencies. In view of the fact that it is impo~tant to count all the pulses, a very high speed comparator, such as an AM685 voltage comparator 142, manufactu~ed by 35 Advanced Micro Devices, 901 Thompson Place, Sunnyvale, ~237539 Califocnia, with emitter-coupled logic (ECL) output, or other suitable very high speed comparator, mu~t be used.
A biasinq neework 141 consisting of a series of resistor6 and capacitocs is used as one input to the COmpaEatOr 142. In view of the fact that the pulses which are handled by the comparatoc 142 are of vecy short duration, a one-shot circuit 14g, compci6ed in the preferred embodiment of the invention, of a Motorola Type 1670 master-slave flip-flop integrated circuit, is used to stretch the pulse width up to a uniform pulse width of approximately 50 nanoseconds. The output signal fco~ the one-shot 144 is fed into a programmable divide-by-N circuit 146, which in the preferred embodiment of the invention is comprised of a Motorola Type 10136 universal hexadecimal counter inteyrated circuit. Th~ divide-by-N ciccuit 146 is pcogrammable.
Accordingly, a vecy high pulse repetition rate co~ing into the comparator with very short pulse widths is re~ormed by the one-shot to have wider, uniform pulses, and thé input signal i6 further reformed by the divide-by-N circuit to bring the pulse cepetition rate down into any desirable range. In particular, outputs of the divide-by-N circuit 146 are provided for N equal to 2, 4, 8, and 16, Up through this point in the circuit, the devices have all been of ECL type in order to be able to handle the very high speed pulses which are detected by the dosimetry probe 58. In view of the fact that it is conventional to use transistor-transistoc-logic (TTL) integrated circuits, a type lOlZ5 ECL-to-TTL level converter circuit 150 is hooked to the output of the divide-by-N circuit 146. Thus, the ECL-to-TTL level converter circuit 150 transforms the ECL signal levPls ~L~37S3~3 into TTL signal leveLs for fulther processinq. The TTLoutputs leave the ECL-to-TTL level conve~te~ circuit 150 5 on four Lines 152, 154, 156, 158, which corcespond to the TTL level of -the~ counts into the Single Channel Analyze~ divided by-~2, 4, 8, and 16. ~espectively. The counts out on the lines 152-158 will be ~efec~ed to hereafter as the ~net counts~.
Multi~liec-Divide~ Ciccuit Referring now to PIG. 8, there is a Multiplie~-Divider circuit 160 which converts the net counts from the Single Channel Analyzer ciccuit, described above, into a meaningful quantity (~illiCu~ies), The Multiplier-Divide~ CilCUit 160 accepts t~e "net count~" on an input line L62 which ifi connected to one of the lines 152-158 from the Single Channel Analyzer (i.e., the raw counts converted into TTL levels and, then divided by 2, 4, 8, or 16) and multiplies them by the eluate Flow Rate divided by 100.
The result is then divided by a constant, K, in orde~ to carcy out the formula:
A (N ) ~ Fl Whe~e, A . total activity (in milliCucies);
N . net count~ (f~om Single Channel Analyzec) P = Plow Rate: and ~ ~ the calibcation factor.
The net counts, N, a~e first multiplied by a two digit numbe~ corEesponding to the eluate Flow Rate (enteced on the Plow Rate thumbwheel switches 112A, 1128, cocresponding to the most significant digit (MSD) and the least significant digit (LSD), cespectively, the 35 thumbwheel switches 112A, L12B a~e on the f~ont panel of - ~37~39 the dosimet~y contr~ller 62, shown in FIG. 3. The multiplication is accomplished by cascading two TTL
5 Synchronous Decade Rate Multiplier circuit~ tF74167).
and sending their output8 th~ough a NAND gate 168. The resulting output corresponds to FoUt, whe~e:
F (N)(F) out 100 The output pulses are of varying duration, so they are next fed through a pair of one-shots which - process them to have a fixed duration. In the preferred embodiment of the invention, the first one-shot is comprised of one-half of an SN14123 integrated circuit 170. The first one-shot is negative edge triggered, and it provides a pulse output of approximately 200 nanoseconds. Its output is double buffered through buf~er~ 172, 174 into a second one-shot which is co~prised of one-half of a CD4098BE integrated circuit 176 in order to increase the width of the output pulses, so they will be acceptable to a CMOS divider integrated circuit 178. The second one-shot is configured to be leading edge triggered.
The output of the second one-shot is then divided by the calibration factor, K, which may have a range of between 3 and 9,999. A CD4059A integrated circuit 178 is used as a programmable divide-by-N
counter. Programming is accomplished via a series of 16 DIP switches 180 mounted on the printed circuit card.
Each set of four switches corresponds to the BCD
settings for l's, lO's, lOO's and lOOO's. Pull up refiistors (not shown) are employed in the standard mannér so that when the DIP switches are open the inputs to the divide-by-N circuit 178 are pulled high.
35` The output of the divider 178 has pulses of 12375;:~9 random widths, so another one-shot. made up of the second half of the CD4098~ 176 configured for leading edge triggecing. is used. This one-shot provides an output pulse duration of approximately 20 microseconds. Before leaving the Multiplier-Divi~er circuit 160, the output is double buffered through buffers 182, 184 and the outpu~ signal on line 186 is sent to the Dose Rate circuit. There will be one dose corrected output pulse on line 186 for each 0.01 milliCurie of activity which passes by the dosimetry probe 58.
DisDlav Controllec Circuit Referring now to FIG. 9, the schematic diagram for a Display Controller Circuit 190 is shown. There are three Display Controller Circuits within the dosimetry controller 62. Each Display Controller 190 is used both to interface a set of thumbwheel switches 192 and to display the guantity associated with the particular set of thumbwheel switches 192. Thus, there i~ one Display Controller of L90 for Dose Rate (which works with thumbwheel switches 102 and LEDs 104), one for Patient Volume (which works with thumbwheel switches 94 and LEDs 96), and one for Dose (which works with thumbwheel switches 98 and LEDs 100). Each Display Controller CiLcuit 190 drives four seven-segment displays 194, such as MAN71 displays.
The major component of the Display Controller Circuit 190 of the preferred embodiment of the invention is an rntersil ICM7217IJI integrated circuit 196, which is a device which provides a direct interface to the seven-segment displays 194. Each ~isplay Controller Circuit 190 allows the user to set a level, by programming binary coded decimal (BCD) thumbwheel switches 192. The levels can then be detected. In this way, a preset limit for Dose, for example, will be 5 detected and will be used to shut down the infusion pump. For Dose Rate, the preset level is used to swi~ch the position of the dive~ter valve 32, through the valve driver circuit which will be explained hereinafter. The Patient Volume can also be preset, and the infusion pump can be stopped at the preset limit.
Dose Rate Circuit The Dose Rate circuit 200, shown in FIG. 10, p{ovides a visual display of the amount of radiation present in the eluate. The Dose Rate circuit 200 employs a Display Controller Circuit, of the type described above. The Dose Rate display is constantly updated to provide the user with Dose Rate information.
The Dose Rate circuit 200, with the Display Controller, is programmed to set a trigger level for switching the eluate from waste to the patient 56.
The Dose Rate circuit 200 uses signals from the Multiplier-Divider circuit 160, described above" and from the Control Board which will be described hereinafter. The dose corrected output pulses on line 186 from the Muitiplier-Divider circuit 160 described above ~i.e., l pulse/.01/mCi) enter the Dose Rate circuit 200, and are double buffered by buffers 202, 204. The buffe~ed pulse~ are then fed through one-half of a one-shot 206, comprised of a CD4098BE integrated circuit in the preferred embodiment of the invention.
The output from the one-shot 206 is gated through NAND
gate 207 to the Dose Rate Display 104 since there are three Display Controller Circuits 190, which are used for Dose (circuit ~'A"), Dose Rate (circuit "B"), and Patien~ Volume (circuit ll~l~), the designation "B10" at 1~:37539 the output of NAND gate 207 means pin 10 on input connector 197 tsee FIG. 9).
The heart of the Dose Rate circuit 200 is an Intersil ICM7207A Oscillator Controller integrated circuit 208. This unit, along with a dual one-shot comprised of a CD4098BE integrated circuit 210, in the preferred embodiment of the invention, provides all of the control necessary for -gating, storing, and resetting the display.
The outputs of the Dose Rate Display Controller Circuit provide an easy inte~face to determine when a predetermined count (corresponding to the dose rate which was ~et on thumbwheel switches 102) has been reached, and to generate a signal which is used for switching the diverter valve 32. The valve switching signal is al~o used to enable the Dose and Patient Volume Displays, 100, 96, respectively.
In the preferred embodiment of the invention, the valve switching signal is derived from one half of a dual D-type flip-flop, such as a CD40138E integrated circuit 212. The flip-flop 212 is only enabled during an injection, i.e., when the infusion pump is being used to either infuse eluate into a patient 56 or to divert it to waste. The enabling "INJECT" signal is generated when the pu~p is injecting. Once an injection is started and a user pre-set Dose Rate limit set on thumbwheel switches 102 is met, the flip-flop 212 latches a positive g output to switch the diverter valve 32 from the waste position to the patient position and to enable the Dose Display and the Patient Volume Display.

~Z37~3~

. Control Circuit Referring now to FIG. 11, the schematic diagram of the Control circuit 220 is shown. The purpose of the Control circuit ~20 is to "oversee" all other operations. Specifically, the Control circuit 220 controls the Dose Display and Patient Volume Display.
The Control circuit 220 also provides timing for resetting the Multiplier-Divider circuit 160, and it buffer~ various~ inputs and outputs to and from the infusion pump control module 60.
The basic function for turning the infusion pump off is the End of Elution signal. The End of Elution signal is derived from either the Dose Display 100 or the Patient Volume Display 96. These displays 100~ 96 are gated to begin counting once the Dose Rate trigger level, the Q output from flip-flop 212, reaches its preset limit, as defined by the Dose Rate thumbwheel switches 102. Then, once the Dose or Patient Volume is met, a~ defined by the Dose thumbwheel switches 98 and by the Patient Volume thumbwheel switches 94, respectively, the Control circuit 220 signals the pump to stop.
Valve Driver Circuit The Valve Driver circuit Z30, shown schematically in FIG. 12, is used to control the switching of the diverter valve 32 which directs the eluate either to the patient 56 or to waste. The Valve Driver circuit 230 accepts its input from the Dose Rate circuit or from the Patient Line Purge Switch 110. The Patient Line Purge Switch 110 directly cont~ols the valve 32.
The diverter valve 32 is a two position valve 35 which includes electrical switches which close 1;~37~39 individually when the valve 32 i8 fully in either the patient or waste position. Movement of the valve 32 s from one po~ition to the other is controlled by an AC
motor which include~ two windings allowing it to be moved in either direction via an AC motor having two windings. When the first winding is energized, the motor move~ in a clockwise direction. When the second winding i8 energized, the motor moves in a counterclockwise direction. At each limit of the valve movement, there is a ~icroswitch 232, 234 which senses when the valve limit has been reached.
When one of the micro6witches 232, 234 is open, i.e. switch 232, the input to an associated inverter 236 is essentially at ground. When the ~witch 232 closes, the input to the inve~ter Z36 increases to approximately five volts. After the switch 232 again opens, it takes some time, due to the RC time constant of the associated resistors and capacitor, before the voltage at the input of the first inverter 236 returns to approximately zero. Accordingly, the co~bination of inverters and the RC network to which each of the switches 232, Z34 are connected acts as a switch debouncer. Thus, the output of inverter 238 will be low when switch 232 is closed and high when switch 232 i8 opened. Similarly, the output of inverter 240 will be low when switch 234 is closéd and high when switch 234 i8 opened.
NAND gate 242 normally has a high output voltage. Accordingly, as will be obvious to those of ordinary skill in the digital circuitry art, LED 106 will be on when switch 232 is closed. Otherwise, LED
106 will be off. Similarly, LED 108 will be on when switch 234 is closed. Note that these LEDs 106, 108 3s were previously described with reference to the 37~

1 ~B70 do~imetry controlleL 62 (See FIG. 3).
When both switches 232, 234 are opened at the ~ame ti~e, there will be two high ~ignals at the input of NAND gate 254. T~at will cause NAND gate 256 to trigger a monostable multivibrator comprised of one half of a CD4098BE integrated circuit 258 which provides a low going output pulæe having a du~ation of approximately 700 milliseconds in the preferred embodiment of the invention. The particular time period during which this pulse is low must exceed the time period which it would take for the diverter valve 32 to be moved from one po~ition to the other position. In the preferred embodiment of the invention the movement of the diverter valve 32 takes approximately 600 milliseconds. The outputs from the monostable multivibrator are fed via~ EXCLUSIVE OR gate 260 into a D-type flip-flop 262 comprised of a CD4013BE integrated circuit. In the event that the diverter valve 32 did not move from one po~ition to the other within the presc~ibed time period, it is presumed that a fault condition occurred, e.g. the diverter valve 32 jammed.
Accordingly, the operator is advised of the fault condit,ion by both LEDs 106, 108 flashing simultaneously. The flashing occurs as a result of the output of the flip-flop 262 which is connected on line 264 to NAND gate 242 belng kept high, thereby causing NAND gate 242 to act as an astable multivibrator which oscillates between high and low outputs thereby causing the EXCLUSIVE OR gates 248, 250 to change states and to flash the LEDs 106, 108.
At the same time that one output of the flip-flop 262 goes high, the other output, on line 266 3s goes low. The signal on line 266 is normally high, as ~Z~37539 .
l RB70 it is one input to NAND gate 268. The other input to NAND gate 26~ is the "End of Elution" signal previously discus~ed. When both inputs to NAND gate 268 are high the output on line 270 is high. The output signal on line 270 turns off the infusion pu~p when it is low.
This i8 the signal which remotely controls the infusion pump, as heretofore described. Thus, in the fault condition, when the signal on line 266 goes low the infusion pump is turned off. When there is no fault condition, the infusion pump will be enabled when the End of Elution signal is high.
The Q output from the dose rate circuit 200 enters the Valve Controller Circuit 230 on line 252. A
series of inverters are used to buffer the Q output in order to obtain an output on line 254. The output on line 254 is used as the input to a pair of solid state relays (not shown) which selects between the two windings of the ~otor which drives the diverter valve 32. Thus, when the Q output is high the motor drives the diverter valve 32 into the Patient position, and when the Q output is low, the motor drives the diverter valve 32 into the Waste position.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A strontium-rubidium infusion system comprising:
(a) means for generating rubidium 82 in a solution which can be infused into a patient;
(b) means for infusing said solution into a patient;
(c) means for measuring the radioactivity present in said solution as it is infused into said patient; and (d) means for controlling said means for infusing in response to the amount of radioactivity which has been infused into said patient.

2. The strontium-rubidium infusion system of Claim 1 wherein said means for generating rubidium 82 in a solution which can be infused into a patient comprises a strontium-rubidium generator.

3. The strontium-rubidium infusion system of Claim 1 wherein said means for infusing said solution into a patient comprises a syringe.

4. The strontium-rubidium infusion system of Claim 3 wherein said means for infusing said solution into a patient further comprises means for electromechanically operating said syringe.

5. The strontium-rubidium infusion system of Claim 4 wherein said means for electromechanically operating said syringe comprises a stepper motor which drives means for moving the plunger of said syringe.

6. The strontium-rubidium infusion system of Claim 5 further comprising electronic means for controlling said stepper motor.

7. The strontium-rubidium infusion system of Claim 1 wherein said means for measuring the radioactivity present in said solution as it is infused into said patient comprises a dosimetry system.

8. The strontium-rubidium infusion system of Claim 7 wherein said dosimetry system is connected to means for controlling said means for infusing.